10,000 days of drugs: Effect of Acetylcholinesteraseinhibitors in real-world data

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-HunKim and Pathfinder team

Nemanja.Vaci@psych.ox.ac.uk

February 2019

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 1 / 19

Introduction

Alzheimer’s dementia research

Two types of drugs have been licensed for the treatment of AD symptoms:

AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)

There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)

Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)

Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19

Introduction

Alzheimer’s dementia research

Two types of drugs have been licensed for the treatment of AD symptoms:

AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)

There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)

Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)

Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19

Introduction

Alzheimer’s dementia research

Two types of drugs have been licensed for the treatment of AD symptoms:

AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)

There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)

Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)

Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19

Introduction

Alzheimer’s dementia research

Two types of drugs have been licensed for the treatment of AD symptoms:

AcEIs (donepezil, rivastigmine, and galantimine) and NMDA receptorantagonist (memantine) (Jindra et al., 2018)

There is evidence of beneficial effect for all these drugs (Farrimond et al., 2012)

Clinical relevance of these drugs is still controversial, due to the smalleffect sizes (Tan et al., 2014)

Clinical trials have good efficacy and internal validity, but theyunderperform on measures of external validity

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 2 / 19

Introduction

Sources of additional evidence: EHRs

UK-CRIS (Clinical Record Interactive Search)

De-identified information from the secondary care services

Information on primary care service through attachments

Data of interest is locked in natural text format

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 3 / 19

Introduction

Sources of additional evidence: EHRs

UK-CRIS (Clinical Record Interactive Search)

De-identified information from the secondary care services

Information on primary care service through attachments

Data of interest is locked in natural text format

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 3 / 19

Introduction

Sources of additional evidence: EHRs

UK-CRIS (Clinical Record Interactive Search)

De-identified information from the secondary care services

Information on primary care service through attachments

Data of interest is locked in natural text format

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 3 / 19

Introduction

The goal

1) NLP models that can extract information of interest from the records

2) Epidemiological analysis on the extracted data

3) Investigate personalised therapies based on the available medical historyin UK-CRIS

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 4 / 19

Introduction

The goal

1) NLP models that can extract information of interest from the records

2) Epidemiological analysis on the extracted data

3) Investigate personalised therapies based on the available medical historyin UK-CRIS

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 4 / 19

New Mind

New Mind 1

Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)

Oxford UK-CRIS Health centre

Rule-based natural language processing model

The algorithms obtained F1 accuracies ranging from 81 to 98%

Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19

New Mind

New Mind 1

Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)

Oxford UK-CRIS Health centre

Rule-based natural language processing model

The algorithms obtained F1 accuracies ranging from 81 to 98%

Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19

New Mind

New Mind 1

Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)

Oxford UK-CRIS Health centre

Rule-based natural language processing model

The algorithms obtained F1 accuracies ranging from 81 to 98%

Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19

New Mind

New Mind 1

Feasibility study:diagnosis of dementia3 drugs (Rivastigmine, Donepezil and Galantamine)2 mental health scores (MMSE and MOCA)

Oxford UK-CRIS Health centre

Rule-based natural language processing model

The algorithms obtained F1 accuracies ranging from 81 to 98%

Epidemiological analysis to investigate deterioration of cognitiveperformance and effect of the drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 5 / 19

Data

Extracted data

Scale: 11298 for 4,521 patients

MMSE MOCA

6,931 4,367

Medication: 32,760 for 3,577 patients

AChEi Donepezil Galantamine Mementine Rivastigmine

1,981 18,341 1,656 7,068 3,714

Diagnosis: 35,010 for 5,740 patients

AD DLB FTD Mixed Other PPD Unspecified VaD

10,723 937 479 600 4 120 18,918 3,229

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 6 / 19

Data

Extracted data

Scale: 11298 for 4,521 patients

MMSE MOCA

6,931 4,367

Medication: 32,760 for 3,577 patients

AChEi Donepezil Galantamine Mementine Rivastigmine

1,981 18,341 1,656 7,068 3,714

Diagnosis: 35,010 for 5,740 patients

AD DLB FTD Mixed Other PPD Unspecified VaD

10,723 937 479 600 4 120 18,918 3,229

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 6 / 19

Data

Extracted data

Scale: 11298 for 4,521 patients

MMSE MOCA

6,931 4,367

Medication: 32,760 for 3,577 patients

AChEi Donepezil Galantamine Mementine Rivastigmine

1,981 18,341 1,656 7,068 3,714

Diagnosis: 35,010 for 5,740 patients

AD DLB FTD Mixed Other PPD Unspecified VaD

10,723 937 479 600 4 120 18,918 3,229

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 6 / 19

Data

Extraction of the time information

Scale: if date is not extracted take the document date

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 7 / 19

Data

Extraction of the time information

Medication: if date is not extracted, use the earliest document date

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 8 / 19

Data

Extraction of the time information

Diagnosis: use the earliest document date

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 9 / 19

Data

MMSE across the time of medication

1968 patients with information on scale and medication

1312 with MMSE and 1008 with MOCA scores

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 10 / 19

Data

Patterns of the data

Number of observations where there is change of drug prescriptions:

No Medication -> AChEi: 877No Medication -> Mementine: 841AChEi -> Mementine: 1098

AChEi -> AChEi: 6463

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 11 / 19

Method

Generalized additive mixed-effect modelling

Nonlinear and linear structure

1) Proposes optimal relation between variables: y = f (x) + e

The magnitude of cognitive deterioration across time

Periods of significant changes in the slope of the nonlinear functions

2) Linear structure has standard general (multilevel) equation

The participants’ intercept is adjusted in all models

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 12 / 19

Results

Effect of medication

Period of changes: - 717 to -136 and 197 to NA (11 months ofstabilization)

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 13 / 19

Results

Effect of medication

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 14 / 19

Conclusion

New Mind 1 conclusions

Distributions of the health scores, diagnosis and medicine (values and timeinformation) gives evidence towards the overall validity of the extractions

Preserving effect of medication on the negative cognitive changesexperienced by patients (Perera et al., 2014)

Improved precision of the time scale on which we capture effects, however,there is need to improve the extractions of different drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 15 / 19

Conclusion

New Mind 1 conclusions

Distributions of the health scores, diagnosis and medicine (values and timeinformation) gives evidence towards the overall validity of the extractions

Preserving effect of medication on the negative cognitive changesexperienced by patients (Perera et al., 2014)

Improved precision of the time scale on which we capture effects, however,there is need to improve the extractions of different drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 15 / 19

Conclusion

New Mind 1 conclusions

Distributions of the health scores, diagnosis and medicine (values and timeinformation) gives evidence towards the overall validity of the extractions

Preserving effect of medication on the negative cognitive changesexperienced by patients (Perera et al., 2014)

Improved precision of the time scale on which we capture effects, however,there is need to improve the extractions of different drugs

Nemanja Vaci, Alejo Nevado-Holgado, Andrey Kormilitzin, Chi-Hun Kim and Pathfinder team10,000 days of drugs 15 / 19